EU/3/16/1701: Orphan designation for the treatment of hyperargininaemia

Hyperargininaemia is one of the inherited disorders known as 'urea-cycle disorders', which cause ammonia and other potentially toxic substances to accumulate in the blood. Patients with hyperargininaemia lack arginase type I, one of the liver enzymes needed to get rid of excess nitrogen. In the absence of this liver enzyme, excess nitrogen accumulates in the body in the form of potentially toxic substances including ammonia, which can be harmful at high levels, especially to the brain. Symptoms of the disease usually appear in the first few years of life and include developmental delay, stiffness especially in the legs, vomiting and seizures (fits).

Hyperargininaemia is a long-term debilitating and life-threatening disease that leads to learning disabilities and is associated with poor overall survival.

At the time of designation, hyperargininaemia affected approximately 0.06 in 10,000 people in the European Union (EU). This was equivalent to a total of around 3,000 people*, and is below the ceiling for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

* Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union (EU 28), Norway, Iceland and Liechtenstein. This represents a population of 513,700,000 (Eurostat 2016).

At the time of designation, glycerol phenylbutyrate (Ravicti) was authorised in the EU for the treatment of urea cycle disorders including hyperargininaemia. Patients were generally advised to control their dietary intake of proteins, which are rich in nitrogen, to reduce the amount of ammonia formed in the body.

The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with hyperargininaemia because early laboratory studies showed that it may reduce levels of arginine, which contains nitrogen. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

This medicine is expected to replace arginase, the enzyme that is lacking in patients with hyperargininaemia. It is thus expected to assist the body to get rid of excess nitrogen, so reducing the amount of potentially toxic substances including ammonia that are produced and therefore the damage to the brain and other organs.

The effects of the medicine have been evaluated in experimental models.

At the time of submission of the application for orphan designation, no clinical trials with the medicine in patients with hyperargininaemia had been started.

At the time of submission, this medicine was not authorised anywhere in the EU for hyperargininaemia. Orphan designation of the medicine had been granted in the USA for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 16 June 2016 recommending the granting of this designation.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• either the rarity of the condition (affecting not more than 5 in 10,000 people in the EU) or insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.